Process for the synthesis of agomelatine

ABSTRACT

Process for the industrial synthesis of the compound of formula (I)

This application is a 371 of PCT/FR12/00005, filed Jan. 4, 2012.

The present invention relates to a new process for the industrialsynthesis of agomelatine, or N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide,of formula (I):

Agomelatine, or N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide, has valuablepharmacological properties.

It has, in fact, the double characteristic of being, on the one hand, anagonist of receptors of the melatoninergic system and, on the otherhand, an antagonist of the 5-HT_(2C) receptor. These properties provideit with activity in the central nervous system and, more especially, inthe treatment of major depression, seasonal affective disorder, sleepdisorders, cardiovascular pathologies, pathologies of the digestivesystem, insomnia and fatigue due to jet-lag, appetite disorders andobesity.

Agomelatine, its preparation and its use in therapeutics have beendescribed in European patent specifications EP 0 447 285 and EP 1 564202.

In view of the pharmaceutical value of this compound, it has beenimportant to be able to produce it using an effective industrialsynthesis process which is readily transferable to the industrial scaleand which provides agomelatine in a good yield and with excellentpurity.

Patent specification EP 0 447 285 describes production of agomelatine ineight steps starting from 7-methoxy-1-tetralone.

In patent specification EP 1 564 202, the Applicant developed a new,much more effective and industrialisable synthesis route in only foursteps starting from 7-methoxy-1-tetralone that makes it possible toobtain agomelatine in highly reproducible manner in a well-definedcrystalline form.

However, the search for new synthesis routes, especially starting fromstarting materials that are less costly than 7-methoxy-1-tetralone, iscurrently still relevant.

The Applicant has continued his investigations and has developed a newprocess for the synthesis of agomelatine starting from allyl cyanide anda xanthate compound: these new starting materials have the advantage ofbeing simple and readily obtainable in large quantities at less cost.

This synthesis route is based on carrying out free radical reactionsthat are not very commonly used but are nevertheless very effective.Converting these reactions to the industrial scale using continuous-flowreactors is promising as it becomes simpler to control propagation ofthe chain reaction.

This new process moreover makes it possible to obtain agomelatine inreproducible manner and without requiring laborious purification, with apurity that is compatible with its use as a pharmaceutical activeingredient. Indeed, agomelatine can accordingly be synthesised in 6steps in the course of which only two of the intermediates are isolated.

More specifically, the present invention relates to a process for theindustrial synthesis of the compound of formula (I):

which process is characterised in that allyl cyanide of formula (II):

is reacted, in the presence of a free radical initiator, with a compoundof formula (III):

wherein Xa represents a group —S—C(S)—OR in which R represents a linearor branched (C₁-C₆)alkyl group,

to yield the compound of formula (IV):

wherein Xa is as defined hereinbefore,

it being possible for this latter compound optionally to be isolated,before being subjected to a cyclisation reaction in the presence of afree radical initiator in order to form the compound of formula (V):

which compound of formula (V) also optionally may be isolated,

which is subjected to a reduction-dehydration reaction to yield thecompound of formula (VI):

which is then subjected to an aromatisation reaction to yield thecompound of formula (VII):

which is subjected to reduction using hydrogen in the presence of Raneynickel in a polar protic medium and to reaction with acetic anhydride toyield the compound of formula (I), which is isolated in the form of asolid.

In a preferred embodiment of the invention, the compound of formula(VII) is then subjected to reduction using hydrogen in the presence ofRaney nickel in an ammoniacal ethanol medium and then converted into asalt using hydrochloric acid to yield the compound of formula (VIII):

which is successively subjected to the action of sodium acetate and thenacetic anhydride to yield the compound of formula (I), which is isolatedin the form of a solid.

Alternatively, the compound of formula (VII) can be subjected toreduction by hydrogen in the presence of Raney nickel in a mediumcomprising acetic anhydride in a polar protic medium to yield thecompound of formula (I), which is isolated in the form of a solid.

In a preferred compound of formula (III), Xa represents a group—S—C(S)—OC₂H₅.

In the processes according to the invention, initiation of the freeradical reactions is carried out by thermal means. Preferably, thereaction mixture is heated to a temperature of from 50° C. to 140° C.Even more preferably, cyclisation is carried out at a temperature offrom 130 to 135° C.

Peroxides are free radical initiators that are especially suitable forcarrying out the step of addition of the compound of formula (II) to thecompound of formula (III), or for performing cyclisation of the compoundof formula (IV) to form the compound of formula (V). By way of example,there may be mentioned, especially, diisobutyryl peroxide, cumylperoxyneodecanoate, tert-amyl peroxyneodecanoate,di(2-ethylhexyl)peroxydicarbonate, tert-butyl peroxyneodecanoate,dibutyl peroxydicarbonate, dicetyl peroxydicarbonate, dimyristylperoxydicarbonate, tert-butyl peroxyneoheptanoate, tert-amylperoxypivalate, didecanoyl peroxide, tert-amyl peroxy-2-ethylhexanoate,tert-butyl peroxyisobutyrate, 1,4-di(tert-butylperoxycarbo)cyclohexane,tert-butyl peroxyacetate, tert-butyl peroxybenzoate, di-tert-amylperoxide, tert-butyl cumyl peroxide, bis(tert-butyl)peroxide, dicumylperoxide, dilauroyl peroxide (DLP) ordi(4-tert-butylcyclohexyl)peroxydicarbonate.

Preferably, the reaction is initiated in the presence of dilauroylperoxide.

The amount of dilauroyl peroxide used in the cyclisation is preferablyfrom 1 to 2.5 equivalents.

In a preferred embodiment of the invention, dilauroyl peroxide is addedto the medium in stages.

The addition and/or cyclisation reactions are carried out in a solventcustomarily used in free radical chemistry such as 1,2-dichloroethane,dichloromethane, benzene, toluene, trifluoromethylbenzene,chlorobenzene, hexane, cyclohexane, heptane, octane, ethyl acetate,tert-butyl alcohol, and mixtures thereof.

Preference is given to using ethyl acetate in the step of addition ofthe compound of formula (II) to the compound of formula (III), whilstcyclisation of the compound of formula (IV) to form the compound offormula (V) is advantageously carried out in chlorobenzene, ethylacetate or ethyl butyrate. In this latter reaction, chlorobenzene ismore especially preferred.

Conversion of the compound of formula (V) into the compound of formula(VI) is advantageously carried out in the presence of a Lewis acid suchas aluminium isopropoxide or samarium isopropoxide. This conversion ismoreover preferably carried out in an alcohol (primary or secondary),and even more preferably in isopropanol.

Preferably, a catalytic amount of p-toluenesulphonic acid is added tothe mixture once all the tetralone (V) has been consumed at the end ofconversion of the compound of formula (V) into the compound of formula(VI).

Aromatisation of compound (VI) is carried out in the presence of aquinone, preferably in the presence of2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) ortetrachlorobenzoquinone (TCQ). Even more preferably, aromatisation iscarried out in the presence of TCQ at the reflux of toluene.

The compound of formula (II) is accessible to the person skilled in theart by means of conventional chemical reactions and/or chemicalreactions described in the literature.

This process is especially valuable for the following reasons:

-   -   it makes it possible to obtain the compound of formula (I) on an        industrial scale in good yields, starting from a simple,        low-cost starting material;    -   only the intermediates of formulae (VI) and (VII) require a        purification and isolation step.

The compounds of formulae (V) and (VI) obtained according to the processof the invention are new and useful as intermediates in the synthesis ofagomelatine.

The Examples hereinbelow illustrate the invention without limiting it inany way. For the purpose of validating the reaction route, the synthesisintermediates were systematically isolated and characterised. However,it is possible to considerably optimise the procedures by limiting thenumber of intermediates isolated. Accordingly, Example 2 givenhereinbelow corresponds to the same reaction route as that used inExample 1 but with the difference that only(7-methoxy-1,2-dihydro-1-naphthyl)acetonitrile and(7-methoxy-1-naphthyl)acetonitrile were isolated.

EXAMPLE 1 N-[2-(7-Methoxy-1-naphthyl)ethyl]acetamide Step A:S-[1-(cyanomethyl)-4-(4-methoxyphenyl)-4-oxobutyl]-O-ethyldithiocarbonate

A solution of allyl cyanide (4.8 mL, 60.0 mmol) andS-[2-(4-methoxyphenyl)-2-oxoethyl]-O-ethyl dithiocarbonate¹ (8.1 g, 30.0mmol) in ethyl acetate (30 mL) is heated at reflux for 15 minutes undera nitrogen atmosphere. There is added, firstly, an amount of dilauroylperoxide (10 mol %) to the solution under reflux. After 1 hour 30minutes, another amount of dilauroyl peroxide (5 mol %) is alsointroduced. When the reagents have been completely consumed, the mixtureis cooled to ambient temperature and concentrated under reducedpressure. The crude mixture is then purified by flash columnchromatography (petroleum ether-ethyl acetate: 95-5 to 80-20) to yieldthe title compound in the form of an oil in a yield of 98%.¹S-[2-(4-methoxyphenyl)-2-oxoethyl]-O-ethyl dithiocarbonate is obtainedaccording to the protocol described in Batanero, B. et al., J. Org.Chem. 2001, 66, 320.

¹H NMR (δ, ppm) 7.93 (m, 2H, CH-4), 6.93 (m, 2H, CH-3), 4.67-4.57 (m,2H, CH₂-13), (CDCl₃, 400 MHz) 3.99 (m, 1H, CH-9), 3.87 (s, 3H, CH₃-1),3.15 (t, 2H, J=7.3 Hz, CH₂-7), 2.95 (dd, 2H, J=17.0, 6.0 Hz, CH₂-10),2.41-2.31 (m, 1H, CH₂-8), 2.19-2.08 (m, 1H, CH₂-8), 1.41 (t, 3H, J=7.1Hz, CH₃-14).

Step B: (7-Methoxy-4-oxo-1,2,3,4-tetrahydro-1-naphthyl)acetonitrile

The compound of Step A, used directly without having been purified, isredissolved in chlorobenzene (900 mL) and the solution is refluxed for15 minutes under a nitrogen atmosphere. Dilauroyl peroxide is thengradually added to the solution under reflux (10 mol % every 10minutes). When the reaction is complete, the mixture is cooled toambient temperature and concentrated under reduced pressure.Acetonitrile is then introduced in order to cause a large part of thedilauroyl peroxide compounds to precipitate out. The mixture is thenfiltered, concentrated under reduced pressure and purified by flashcolumn chromatography (petroleum ether-ethyl acetate: 60-40) to yieldthe title compound in solid form in a yield of 40%.

HRMS (EI, m/z) Calc. for C₁₃H₁₃NO₂: 215.0946; found: 215.0946.

Step C: (7-Methoxy-1,2-dihydro-1-naphthyl)acetonitrile

Aluminium isopropoxide (2.05 g, 10.0 mmol) is added to a solution of thecompound obtained in Step B (680 mg, 3.15 mmol) in isopropanol (15 mL)at ambient temperature. The reaction mixture is refluxed. When thereagents have been completely consumed, a few crystals ofp-toluenesulphonic acid monohydrate are added and a Dean-Stark apparatusis mounted on top of the flask. The mixture is again refluxed for 1hour, during which the isopropanol is gradually replaced with toluene bymeans of the Dean-Stark apparatus. A 1N HCl solution is then added andthe resulting phases are separated. The aqueous phase is extracted withethyl acetate, the organic phases being washed with saturated NaHCO₃solution and with saturated NaCl solution, then dried over MgSO₄,filtered and concentrated under reduced pressure. The residue ispurified by column chromatography (petroleum ether-ethyl acetate: 80-20)to yield the title product in the form of an oil in a yield of 85%.

HRMS (EI, m/z) Calc. for C₁₃H₁₃NO: 199.0997. found: 199.1001.

Step D: (7-Methoxy-1-naphthyl)acetonitrile

Method A:

To a solution of the compound obtained in Step C (1.0 g, 5.0 mmol) indichloromethane (50 mL) at ambient temperature there is added DDQ (1.4g, 6.0 mmol). The reaction mixture is stirred for 2 days and is thenwashed with saturated NaHCO₃ solution. The aqueous phase is extractedwith ethyl acetate, the organic phase being washed with saturated NaClsolution, dried over MgSO₄, filtered and concentrated under reducedpressure. The residue is purified by column chromatography (petroleumether-ethyl acetate: 80-20) to yield the title product in solid form ina yield of 55%.

Method B:

To a solution of TCQ (615 mg, 2.5 mmol) in toluene (1.5 mL) heated to80° C. there is added the compound obtained in Step C (462 mg, 2.3 mmol)dissolved in toluene (3.5 mL). The mixture is then refluxed for 2.5hours and is then diluted with water and extracted with petroleum ether.The organic phase is washed with NaOH solution (30% by weight) and withwater and is then dried over MgSO₄, filtered and concentrated underreduced pressure. The residue is purified by column chromatography(petroleum ether-ethyl acetate: 80-20) to yield the title product insolid form in a yield of 61%.

HRMS (EI, m/z) Calc. for C₁₃H₁₁NO: 197.0841. found: 197.0838.

Step E: N-[2-(7-Methoxy-1-naphthyl)ethyl]acetamide

The reaction was carried out on a larger batch in order to optimise theyield obtained: 136 g of Raney nickel, 2.06 L of ethanol and 0.23 L ofwater are introduced into an 8 L reactor. Whilst stirring at 70° C. andunder 30 bars of hydrogen, the compound obtained in Step D (0.8 kg)dissolved in acetic anhydride (2.4 L) is slowly added. At the end of theaddition, the reaction mixture is stirred for 1 hour under hydrogen at30 bar, the reactor is then decompressed and the liquors are filtered.After concentration of the mixture, the residue is crystallised from amixture of ethanol/water 35/65 to yield the title product in a yield of89% and with a chemical purity greater than 99%.

Melting point: 108° C.

EXAMPLE 2 N-[2-(7-ethoxy-1-naphthyl)ethyl]acetamide Step A:(7-Methoxy-1,2-dihydro-1-naphthyl)acetonitrile

A solution of allyl cyanide (6.75 mL, 84.0 mmol) andS-[2-(4-methoxyphenyl)-2-oxoethyl]-O-ethyl dithiocarbonate¹ (11.3 g,42.0 mmol) in ethyl acetate (45 mL) is heated at reflux for 15 minutesunder a nitrogen atmosphere. There is added, firstly, an amount ofdilauroyl peroxide (10 mol %) to the solution under reflux. After 1 hour30 minutes, another amount of dilauroyl peroxide (5 mol %) is alsointroduced. When the reagents have been completely consumed, the mixtureis cooled to ambient temperature and concentrated under reducedpressure. The crude mixture is redissolved in chlorobenzene (640 mL) andthe solution is refluxed for 15 minutes under a nitrogen atmosphere.Dilauroyl peroxide is then gradually added to the solution under reflux(10 mol % every 10 minutes). When the reaction is complete, the mixtureis cooled to ambient temperature and concentrated under reducedpressure. Acetonitrile is then introduced in order to cause a large partof the dilauroyl peroxide compounds to precipitate out. The mixture isthen filtered and concentrated under reduced pressure. Half the crudeoil thereby obtained is redissolved in isopropanol (100 mL) at ambienttemperature in the presence of aluminium isopropoxide (13.6 g, 66.6mmol). The reaction mixture is refluxed. When the reagents have beencompletely consumed, a few crystals of p-toluenesulphonic acidmonohydrate are added and a Dean-Stark apparatus is mounted on top ofthe flask. The mixture is again refluxed for 2 hours, during which theisopropanol is gradually replaced with toluene by means of theDean-Stark apparatus. A 1N HCl solution is then added and the resultingphases are separated. The aqueous phase is extracted with ethyl acetate,the organic phases being washed with saturated NaHCO₃ solution and withsaturated NaCl solution, then dried over MgSO₄, filtered andconcentrated under reduced pressure. The residue is purified by columnchromatography (petroleum ether-ethyl acetate: 80-20) to yield the titleproduct in the form of an oil in a yield of 24%.

HRMS (EI, m/z) Calc. for C₁₃H₁₃NO: 199.0997. found: 199.1001.

Step B: (7-Methoxy-1-naphthyl)acetonitrile

The procedure is analogous to Step D of Example 1.

Step C: N-[2-(7-Methoxy-1-naphthyl)ethyl]acetamide

The procedure is analogous to Step E of Example 1.

The invention claimed is:
 1. A process for the synthesis of a compoundof formula (I):

wherein allyl cyanide of formula (II):

is reacted, in the presence of a free radical initiator, with a compoundof formula (III):

wherein Xa represents a group —S—C(S)—OR in which R represents a linearor branched (C₁-C₆)alkyl group, to yield the compound of formula (IV):

wherein Xa is as defined hereinbefore, wherein this latter compound maybe optionally isolated, before being subjected to a cyclisation reactionin the presence of a free radical initiator in order to form thecompound of formula (V):

which compound of formula (V) may also be optionally isolated, whichcompound of formula (V) is subjected to a reduction-dehydration reactionto yield the compound of formula (VI):

which is then subjected to an aromatisation reaction to yield thecompound of formula (VII):

which is subjected to reduction using hydrogen in the presence of Raneynickel in a polar protic medium and to reaction with acetic anhydride toyield the compound of formula (I), which is isolated in the form of asolid.
 2. The process according to claim 1, wherein the compound offormula (VII) is subjected to reduction using hydrogen in the presenceof Raney nickel in an ammoniacal ethanol medium and then converted intoa salt using hydrochloric acid to yield the compound of formula (VIII):

which is successively subjected to the action of sodium acetate and thenacetic anhydride to yield the compound of formula (I), which is isolatedin the form of a solid.
 3. The process according to claim 1, wherein thecompound of formula (VII) is subjected to reduction by hydrogen in thepresence of Raney nickel in a medium comprising acetic anhydride in apolar protie medium to yield the compound of formula (I), which isisolated in the form of a solid.
 4. The process according to claim 1,wherein the group Xa represents —S—C(S)—OC₂H₅.
 5. The process accordingto claim 1, wherein the free radical reactions are initiated by thermalmeans at a temperature of from 50 to 140° C.
 6. The process according toclaim 1, wherein cyclisation of the compound of formula (IV) is carriedout at a temperature of from 130 to 135° C.
 7. The process according toclaim 1, wherein the step of addition of the compound of formula (II) tothe compound of formula (III) and that of cyclisation of the compound offormula (IV) are initiated in the presence of dilauroyl peroxide.
 8. Theprocess according to claim 1, wherein the step of addition of thecompound of formula (II) to the compound of formula (III) is carried outin chlorobenzene.
 9. The process according to claim 1, wherein the stepof cyclisation of the adduct of formula (IV) to form the compound offormula (V) is carried out in ethyl acetate.
 10. The process accordingto claim 1, wherein the conversion of the compound of formula (V) intothe compound of formula (VI) is carried out in the presence of aluminiumisopropoxide.
 11. The process according to claim 1, wherein theconversion of the compound of formula (V) into the compound of formula(VI) is carried out in isopropanol.
 12. The process according to claim1, wherein a catalytic amount of p-toluenesulphonic acid is added to themixture at the end of conversion of the compound of formula (V) into thecompound of formula (VI).
 13. The process according to claim 1, whereinthe aromatisation of the compound of formula (VI) is carried out in thepresence of a quinone.
 14. The process according to claim 1, wherein thearomatisation of the compound of formula (VI) is carried out in thepresence of TCQ at the reflux of toluene.
 15. A process for thesynthesis of agomelatine starting from the compound of formula (V):

wherein the compound of formula (V) is obtained according to the processaccording to claim
 1. 16. A process for the synthesis of agomelatinestarting from the compound of formula (VI):

wherein the compound of formula (VI) is obtained according to theprocess according to claim
 1. 17. A compound of formula (V):


18. A compound of formula (VI):